IMAGINE walking through an unfamiliar city on the lookout for a place to eat. You come across a beguiling venue with a menu by the door, rave reviews posted in the windows and a friendly waiter eager to show you to a table. You walk in and – Slam! – the door shuts behind you and heavy bolts slide into place. You find yourself in a bare room with no way out.
You would be hugely unlucky if it actually happened to you, but for the bugs that invade your body this may become a familiar experience. Two teams of biologists – one at the University of Massachusetts and the other at Yale University – are independently hunting for ways to spring this trap on viruses such as HIV. Using a little molecular chicanery, they believe they can lure viruses into decoy “restaurants” and entrap them for good.
The strategy is as dastardly as it is straightforward. In order to reproduce, a virus must invade a host cell and hijack its DNA-replication machinery. But what if the cell were a decoy with no such machinery inside? Invading the cell would take a virus out of circulation for good.
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In the never-ending arms race between bugs and drugs, these “virus traps” could provide a new type of weapon. Although traps alone would probably not be enough to vanquish a virus as prolific and evasive as HIV, they could help reduce viral load enough to give a besieged immune system the chance to recover. Best of all, it’s hard to see how a virus could evolve resistance to a trap.
Virus trapping may be a new strategy in medicine but it is one of nature’s oldest tricks. Mucins, proteins that are found in most body secretions including mucus and breast milk, are coated with sugar chains called glycans designed to trick and trap invading pathogens, says biologist Pascal Gagneux of the University of California, San Diego.
Another possible trap is red blood cells. All cells, including red blood cells, are covered with glycans too. The precise function of most of these is unknown, but they seem to be involved in cell-to-cell communication. Unfortunately, glycans are also used by viruses as entry points to insinuate themselves into target cells.
In 1999, Gagneux and colleague Ajit Varki proposed that one function of red blood cells is to act as decoys, using glycans to take viruses out of circulation (). The idea makes sense. Mature red blood cells lack DNA or replication machinery, so would be a dead end for any viral invader. The function of their surface glycans is otherwise unknown – people who lack them because of a genetic defect do not appear to suffer ill-effects. Red blood cells are also bountiful, circulate into every nook and cranny of the body, and survive for only about 120 days before being sent to the spleen, liver or bone marrow for destruction. Any virus that attacked a red blood cell would first become trapped and, shortly after, scrapped.
In 2002, a team led by David Conway at the London School of Hygiene and Tropical Medicine came up with more evidence that red blood cells may be natural pathogen traps. Glycans are attached to red blood cells by a cell-surface glycoprotein called glycophorin A, which also acts as a receptor for the malaria parasite Plasmodium falciparum. Since the protein confers a vulnerability to malaria, Conway’s team wanted to know why it has not been altered by evolution. On discovering that glycophorin A also binds many viruses and bacteria – among them influenza, reoviruses and the pneumonia-causing bacterium Mycoplasma pneumoniae – they argued that the glycoprotein’s job is to be a lure. That could explain why it has been conserved: its usefulness in everyday pathogen patrol outweighs its risks ().
The idea that red blood cells are natural pathogen traps is promising but remains unproven, says Gagneux. Even if they are not, Robert Finberg of the University of Massachusetts Medical School in Worcester believes they can be customised to do the job. He got the idea from decades spent exploring the role of cell surface receptors in interactions between pathogens and their hosts. “I started to think about how we might actually use these receptors, since we could manipulate the proteins,” he says.
“Even if red blood cells are not natural virus traps, they could be customised to do the job”
A few years ago, Finberg’s team set about testing whether a mouse’s red blood cells could be turned into virus traps. They genetically engineered mice to produce red cells with an unusual receptor on their surface, the coxsackie and adenovirus receptor (CAR) ().
CAR appears to be involved in fetal organ development and is found on the surface of many cell types – though not red blood cells. As its name suggests, CAR is also the receptor that a group of viruses called the coxsackieviruses use to infect cells. In humans, coxsackieviruses can cause a range of illnesses from the common cold to encephalitis, hepatitis and myocarditis. In mice, such infections are swift and often fatal. The virus first invades the pancreas, where it multiplies rapidly, then spreads to other organs through the bloodstream.
To see if red blood cells equipped with CAR could act as coxsackievirus traps, Finberg’s team took blood from the modified mice and tested its ability to mop up a type of coxsackievirus called CVB. The results were striking. The modified red blood cells rapidly neutralised the virus, reducing viral levels by 90 per cent in just 10 minutes and clearing it out completely in an hour. That is as powerful as the immune system’s own precision weapon, neutralising antibodies.
So far so good. But would it work inside live mice, where the virus might invade CAR-studded organs before red blood cells had a chance to intervene? Finberg’s team infected modified and regular mice with CVB. Again, the results were encouraging. Within 24 hours, CVB was running rampant in the plasma of unmodified mice but was concentrated in the red blood cells of modified ones. After 72 hours, organ samples showed that the modified mice had only 10 per cent of the virus loads of normal mice. By day 5, half of the normal mice had died and by day 14 they were all dead. However, no modified mice died until day 7, and one-third of them survived to the end of the two-week experiment.
Nanoparticles to the rescue
Virus trapping clearly works, but the leap from creating transgenic mice to manufacturing red blood cell traps for use in humans is a daunting one. So Finberg’s team has shifted its focus away from red blood cells to synthetic traps. The new goal is to develop nanoparticles coated with viral receptors that can be manufactured quickly and in large quantities. “This is a lot simpler,” Finberg says.
His team plans to start testing nanotraps in mice in a few months, initially to determine which materials work and at what doses. Among the possibilities are biodegradable plastics, iron oxide and magnetite.
There are some big questions to be answered too. Viruses and other pathogens exploit cell receptors that evolved for more benign purposes, such as communication between cells. The danger is that an infusion of virus traps bristling with decoy receptors would interfere with these important communication systems.
While this is an issue for pathogen traps in general, it is particularly acute for nanotraps. At just 150 nanometres across – a tiny fraction of the size of a red blood cell – nanotraps may sidle into places that red blood cells can’t reach: they may even cross the blood-brain barrier. Gagneux warns that circulating nanotraps could interfere with important “crosstalk” in processes such as immune function and the growth of new nerve cells.
However, if nanotraps can be finely tuned to focus exclusively on their prey, the fact that they cross the blood-brain barrier means they could provide a new way to treat neurological illnesses such as viral encephalitis. “In many ways we’d like them to cross the blood-brain barrier. That’s a plus,” says Finberg.
Tackling the issue from a different perspective is ecologist Paul Turner of Yale University. To him, a virus trap is an example of an “ecological trap” – a habitat that looks fertile but is actually a blind alley. The classic example is mayflies mistaking asphalt for water and laying their eggs on it. In nature, ecological traps can cause local populations to decline, or even die out if they outnumber fertile habitats. Turner wanted to know under what conditions artificial virus traps could do the same, so he created a mini-ecosystem made up of the bacterium Pseudomonas syringae and a virus called phi 6, which preys on it ().
He chose this system because it is easy to introduce a trap. To attack Pseudomonas, phi 6 first latches onto telescopic appendages called pili, which the bacterium uses to invade plants. When the pili are retracted, the virus is pulled inside. However, there is a mutant “superpiliated” strain of Pseudomonas which has more pili than normal but cannot retract them, meaning phi 6 can bind to but cannot enter and infect the bacterium. This is the strain used to trap would-be invaders.
Attacking HIV
To test its effectiveness, Turner prepared test tubes of the bacterium with varying levels of trap, then introduced the virus. “We set up a game playing by the simplest rules possible,” he explains. He judged success or failure by viral survival and growth rates. If the trap works, virus levels should decline – which is exactly what happened. A 50:50 mix of traps and normal bacteria vanquished phi 6 completely.
Turner’s team is now looking to turn experiment into therapy, removing red blood cells and adding decoy attachment sites for viruses. Their focus right now is HIV. “All of our drugs against HIV are effective because they keep immune cell counts up,” says Turner. “That’s a very expensive venture that a lot of people can’t afford. If you could find a way to protect those cells through a sheer onslaught of traps, that might be another way to achieve the same thing.”
Off-the-shelf traps for any given virus are years away. But if this strategy works, the pay-off would be huge. It would be easier and faster to ramp up production of traps than building up vaccine stocks. Traps could also be designed for use against any virus – and possibly bacteria and protozoans, too – that use a receptor to break and enter.
Perhaps best of all, unlike with antibiotics, it would be difficult to evolve resistance to a virus trap. If a virus loses its affinity for the receptor, it also forfeits its ability to infect viable hosts. In the ongoing war between pathogens and hosts, weapons of mass deception could be a new winning strategy.
